The Branch has devoted most of its attention to the longitudinal study of individuals "at risk" for developing Alzheimer?s disease (AD). Having recruited over 200 subjects who have a positive family history of AD or are age-matched controls, the study (95-M-096) is aimed at detecting early markers that might hint at the underlying development of AD before the clinical diagnosis would otherwise be apparent. To accomplish this task, the GPB has done extensive baseline assessments of these individuals from medical, psychological, neuropsychological, brain imaging and biological perspectives. Once entered into the study, individuals return on an annual basis for follow up evaluations to track any interval change and to assess the biologic patterns of these markers over time in normal as well as pre-Alzheimer subjects and known AD subjects also being followed longitudinally. Previously published data has showed that cerebrospinal fluid (CSF) is a major source of information about the biochemistry of AD. In fact, CSF ?-amyloid and tau proteins have been suggested as important "biomarkers" because of their central role in the pathologic definition of the illness at autopsy. In a group of mild-to-moderate AD subjects followed over several years, CSF tau was found to be elevated compared to controls but stable over time, at least in the middle phases of the illness (Sunderland et al. 1999). We are now examining the CSF levels of ?-amyloid and tau in the "at risk" individuals and finding that while mean levels are not significantly different in group comparisons, when the "at risk" individuals are divided by their Apo E4 allele status, there is a significant difference in ?-amyloid levels between those who are APO E4(+) and APO E4(-) (Sunderland et al. 2001). In the neuroimaging section of the GPB, Dr. Robert Cohen has found with serial measures on MRI scans that the hippocampal volume in the APO E4 (+) females decreases faster over time than that of the APO E4 (-) females (Cohen et al., In Press). Therefore, it appears that even before there is phenotypic evidence of disease, these individuals are showing signs of change which are characteristic but not necessarily diagnostic of AD. It is for this reason that these subjects are extremely valuable for future study in this ongoing project. The GPB has also recently completed a follow up study of bereavement in the elderly. Over seventy-five subjects and controls were studied for 13 months after the loss of their spouse, and they were tested for evidence of psychological and immunological change during that time. Approximately 25% of the bereaved subjects suffered from symptoms of major depression during the follow up study and met criteria for clinical treatment. While there were some biological changes associated with the mood shifts seen during the course of the study, there was no single pattern of events that presaged the immunologic alterations, although it was noted that subjects with "traumatic grief" were the most affected (Khin et al, under review). Treatment groups were relatively small, so therapeutic differences amongst the various pharmacologic agents was impossible to discern. This study is now in the final stages of completion.